Do colorectal cancer patients diagnosed as an emergency differ from non-emergency patients in their consultation patterns and symptoms? A longitudinal data-linkage study in England.

BACKGROUND: More than 20% of colorectal cancers are diagnosed following an emergency presentation. We aimed to examine pre-diagnostic primary-care consultations and related symptoms comparing patients diagnosed as emergencies with those diagnosed through non-emergency routes. METHODS: Cohort study of colorectal cancers diagnosed in England 2005 and 2006 using cancer registration data individually linked to primary-care data (CPRD/GPRD), allowing a detailed analysis of clinical information referring to the 5-year pre-diagnostic period. RESULTS: Emergency diagnosis occurred in 35% and 15% of the 1029 colon and 577 rectal cancers. 'Background' primary-care consultations (2-5 years before diagnosis) were similar for either group. In the year before diagnosis, >95% of emergency and non-emergency presenters had consulted their doctor, but emergency presenters had less frequently relevant symptoms (colon cancer: 48% vs 71% (P<0.001); rectal cancer: 49% vs 61% (P=0.043)). 'Alarm' symptoms were recorded less frequently in emergency presenters (e.g., rectal bleeding: 9 vs 24% (P=0.002)). However, about 1/5 of emergency presenters (18 and 23% for colon and rectal cancers) had 'alarm' symptoms the year before diagnosis. CONCLUSIONS: Emergency presenters have similar 'background' consultation history as non-emergency presenters. Their tumours seem associated with less typical symptoms, however opportunities for earlier diagnosis might be present in a fifth of them.

Differential pulse oximetry readings between ethnic groups and delayed transfer to intensive care units.

BACKGROUND: Pulse oximeters are widely used to monitor blood oxygen saturations, although concerns exist that they are less accurate in individuals with pigmented skin. AIMS: This study aimed to determine if patients with pigmented skin were more severely unwell at the period of transfer to intensive care units (ICUs) than individuals with White skin. METHODS: Using data from a large teaching hospital, measures of clinical severity at the time of transfer of patients with COVID-19 infection to ICUs were assessed, and how this varied by ethnic group. RESULTS: Data were available on 748 adults. Median pulse oximetry demonstrated similar oxygen saturations at the time of transfer to ICUs (Kruskal-Wallis test, P = 0.51), although median oxygen saturation measurements from arterial blood gases at this time demonstrated lower oxygen saturations in patients classified as Indian/Pakistani ethnicity (91.6%) and Black/Mixed ethnicity (93.0%), compared to those classified as a White ethnicity (94.4%, Kruskal-Wallis test, P = 0.005). There were significant differences in mean respiratory rates in these patients (P < 0.0001), ranging from 26 breaths/min in individuals with White ethnicity to 30 breaths/min for those classified as Indian/Pakistani ethnicity and 31 for those who were classified as Black/Mixed ethnicity. CONCLUSIONS: These data are consistent with the hypothesis that differential measurement error for pulse oximeter readings negatively impact on the escalation of clinical care in individuals from other than White ethnic groups. This has implications for healthcare in Africa and South-East Asia and may contribute to differences in health outcomes across ethnic groups globally.

Aspirin and other non-steroidal anti-inflammatory drug use and colorectal cancer survival: a cohort study.

BACKGROUND: Aspirin has been widely reported to reduce the incidence of colorectal cancer. Recently, a survival benefit after diagnosis has also been suggested. Data regarding such a benefit are to date contradictory. This study examines the effect of non-steroidal anti-inflammatory drug (NSAID) use on mortality in colorectal cancer in a larger patient cohort than previously to further clarify this effect, especially in terms of exposure timing and dosing. METHODS: A study using the General Practice Research Database assessed whether aspirin or NSAID exposure in the year immediately following diagnosis affected all-cause mortality in a cohort of 13 994 colorectal cancer patients. Cox proportional hazards modelling adjusted for age, gender, smoking, body mass index and comorbidity. RESULTS: Overall mortality was slightly lower in patients treated with aspirin, (hazard ratio (HR)=0.91; 95% confidence interval (CI)=0.82-1.00). This effect was observed only in patients treated with prophylaxis-dose aspirin (HR=0.89, CI=0.80-0.98) and only in patients taking aspirin before diagnosis (HR=0.86, CI=0.76-0.98). Differential effects were observed depending on the time after diagnosis. Up to 5 years, a reduction in mortality was observed for aspirin users (HR=0.83, CI=0.75-0.92), whereas after 10 years there was an increase in mortality (HR=1.94, CI=1.26-2.99). For NSAID use, no significant effect was observed on overall mortality (HR=1.07, CI=0.98-1.15). High-dose NSAID use was associated with a slight increase in mortality (HR=1.41, CI=1.26-1.56). INTERPRETATION: These findings provide further indication that aspirin may be beneficial in reducing mortality in colorectal cancer during the first 5 years. The same cannot be said for other NSAIDs, where a small increase in mortality was observed.

Tricyclic antidepressants and the incidence of certain cancers: a study using the GPRD.

BACKGROUND: Several studies suggest links between cancer and tricyclic antidepressant use. METHODS: A case-control study using the General Practice Research Database examined whether previous tricyclic usage was associated with reduced incidence of brain (with glioma as a sub-category), breast, colorectal, lung and prostate cancers. Conditional logistic regression adjusted for age, gender, general practice, depression, smoking, body mass index, alcohol use and non-steroidal anti-inflammatory drug use. RESULTS: A total of 31 953 cancers were identified, each matched with up to two controls. We found a statistically significant reduction in tricyclic prescriptions compared with controls in glioma (odds ratio (OR) =0.59, 95% confidence interval (CI)=0.42-0.81) and colorectal cancer patients (OR=0.84, CI=0.75-0.94). These effects were dose-dependent (P-values for trend, glioma=0.0005, colorectal=0.001) and time-dependant (P-values for trend glioma=0.0005, colorectal=0.0086). The effects were cancer-type specific, with lung, breast and prostate cancers largely unaffected by antidepressant use. CONCLUSION: The biologically plausible, specific and dose- and time-dependant inverse association that we have found suggests that tricyclics may have potential for prevention of both colorectal cancer and glioma.

The antecedents of biliary cancer: a primary care case-control study in the United Kingdom.

In a case-control study using a large UK primary care database, we found that non-steroidal anti-inflammatory drugs had no protective effect against biliary carcinomas (cholangiocarcinoma and gall bladder cancer). Increased risks were observed for cigarette smoking, diabetes, gallstone disease and obesity.

Obesity and type 2 diabetes are important risk factors underlying previously undiagnosed cirrhosis in general practice: a cross-sectional study using transient elastography.

BACKGROUND: Rising cirrhosis incidence and mortality in the United Kingdom has been attributed predominantly to excess alcohol consumption. However, metabolic risk factors such as Type 2 diabetes and obesity may also be important. AIM: To screen at-risk individuals in general practice for undetected cirrhosis using transient elastography and study the risk factors underlying these cases. METHODS: The study was undertaken in 4 general practices (adult patient population 20 868) between February 2012 and September 2014. Patients with defined risk factors for chronic liver disease (hazardous alcohol use and/or Type 2 diabetes) were identified from the General Practice electronic records and invited for transient elastography. Elevated liver stiffness was defined as ≥8 kPa. Cirrhosis was confirmed by established histological, radiological and biochemical methods. RESULTS: Two thousand three hundred and sixty eight patients were invited for transient elastography and 899/919 who attended (97.8%) had valid measurements. Of these 230 patients had elevated liver stiffness (25.6%) and 27 had cirrhosis (2.9%). Risk factors for new cirrhosis diagnoses were obesity and/or Type 2 diabetes in 16 patients (59.3%), alcohol alone in 3 (11.1%) and both alcohol and obesity and/or diabetes in eight (29.6%). Presence of cirrhosis was significantly increased in obese patients with Type 2 diabetes or hazardous alcohol use compared to non-obese (odds ratio 9.4 [95% CI 2.2-40.9] and 5.6 [95% CI 1.6-19.7] respectively). CONCLUSIONS: The number of new cases of cirrhosis diagnosed clearly demonstrates that existing estimates of prevalence are likely to be gross underestimates. Obesity was an important risk factor for cirrhosis within both alcohol users and diabetics.

Risk of hepatocellular carcinoma among individuals with different aetiologies of cirrhosis: a population-based cohort study.

BACKGROUND: Among patients with cirrhosis, only those determined to be at risk for hepatocellular carcinoma (HCC) should undergo surveillance. However, little is known about how different aetiologies of cirrhosis affect risk for HCC. AIM: To quantify the cumulative incidence of HCC among a representative population of people with cirrhosis of the liver of varying aetiology. METHODS: We identified subjects with hepatic cirrhosis from the UK's General Practice Research Database (1987-2006). Diagnoses of HCC were obtained from linked national cancer registries (1971-2006). Cox proportional hazards regression was used to estimate hazard ratios. The predicted 10-year cumulative incidence of HCC for each aetiology of cirrhosis was estimated while accounting for competing risks of death from any cause and liver transplant. RESULTS: Among 3107 people with cirrhosis, the adjusted relative risk of HCC was increased twofold to threefold among people with viral and autoimmune/metabolic aetiologies, compared to those with alcohol-associated cirrhosis. The 10-year predicted cumulative incidence estimates of HCC for each aetiology were alcohol, 1.2%; chronic viral hepatitis, 4.0%; autoimmune or metabolic disease, 3.2%; and cryptogenic, 1.1%. CONCLUSIONS: In a population-based study in the UK, people with cirrhosis have an estimated cumulative 10-year incidence of HCC of 4% or lower. Cumulative incidence varies with aetiology such that individuals with alcohol or cryptogenic cirrhosis have the lowest risk for HCC. These findings provide important information for cost-effectiveness analyses of HCC surveillance.

Risk of schizophrenia in people with coeliac disease, ulcerative colitis and Crohn's disease: a general population-based study.

BACKGROUND: Recently, interest has been revived in whether people with coeliac disease, in contrast to other inflammatory gastrointestinal diseases, have an increased risk of schizophrenia. AIM: To compare the risk of schizophrenia in people diagnosed with coeliac disease, ulcerative colitis and Crohn's disease with the general population. METHODS: We used data from the UK General Practice Research Database. People with coeliac disease, Crohn's disease and ulcerative colitis were matched individually with five age-, sex- and general practice-matched controls. The prevalence of schizophrenia was calculated and compared between disease groups and their respective controls. We calculated odds ratios for schizophrenia using conditional logistic regression adjusting for smoking status. RESULTS: In people with coeliac disease, Crohn's disease and ulcerative colitis the prevalence of schizophrenia was 0.25%, 0.27% and 0.24%, respectively, compared with a general population prevalence of 0.37%. The adjusted odds ratios showed no association between schizophrenia and gastrointestinal disease (coeliac disease vs. controls 0.76, 95% CI: 0.41-1.4; Crohn's disease vs. controls 0.74, 95% CI: 0.44-1.3; ulcerative colitis 0.71, 95% CI: 0.44-1.1). CONCLUSIONS: Contrary to recent findings we found no evidence of an increased risk of schizophrenia in people with coeliac disease compared with the general population.

Is an internal comparison better than using national data when estimating mortality in longitudinal studies?

BACKGROUND: Discrepancies between the results of different studies looking at mortality in similar disease cohorts led us to consider the impact of methodology upon outcome. METHODS: Cohort studies were carried out using age, sex, practice, and calendar time matched control groups in the general practice research database. Data were used on all subjects with inflammatory bowel disease, coeliac disease, or Barrett's oesophagus. Mortality data for the population of England and Wales were obtained from the UK Office for National Statistics. The study compared hazard ratios (HR) for mortality using the matched controls to those found when an indirect standardisation to the mortality experience of England and Wales was carried out. RESULTS: For all three conditions the mortality risk was slightly lower when the national population data were used compared with the internal comparison group (coeliac disease HR 1.33 v standardised mortality ratios (SMR) 1.25, Barrett's oesophagus HR 1.32 v SMR 1.32, inflammatory bowel disease HR 1.50 v SMR 1.34). CONCLUSIONS: A bias was found towards underestimating mortality risk when cohort studies use national population death rates as a comparator. Estimates obtained when an internal comparison group has been used are probably more appropriate.

Dose-finding, safety, and tolerability study of an oral platelet glycoprotein IIb/IIIa inhibitor, lotrafiban, in patients with coronary or cerebral atherosclerotic disease.

BACKGROUND: Antiplatelet therapy is the mainstay of the treatment and secondary prevention of cardiovascular and cerebrovascular ischemic events. We assessed the safety, tolerability, and pharmacodynamics of lotrafiban, an oral platelet glycoprotein IIb/IIIa inhibitor, as a secondary prevention strategy in patients with cerebrovascular or cardiovascular disease. METHODS AND RESULTS: Overall, 451 patients with a recent cardiovascular or cerebrovascular acute ischemic event were randomized in a double-blind fashion to 1 of 5 dosing regimens for 12 weeks: placebo or 5, 20, 50, or 100 mg lotrafiban, both twice daily with 300 to 325 mg/d aspirin. The primary end point was the incidence and tolerability of major and minor bleeding during treatment. Secondary end points included inhibition of platelet aggregation and clinical events. The placebo and lotrafiban 5-mg groups had similarly low rates of minor and major bleeding, but the 100-mg arm was terminated early because of excess major bleeding. Protocol-defined thrombocytopenia (<100 000 platelets/microL) occurred in 5 lotrafiban-treated patients (1.4%, 95% CI 0.2% to 2.7%) and 1 placebo patient (1.1%, 95% CI 0% to 3.1%). Three lotrafiban-treated patients had a nadir platelet count <20 000/microL (0.9%, 95% CI 0% to 1.8%). Lotrafiban produced dose-dependent inhibition of platelet aggregation; 5 mg lotrafiban did not differ significantly from placebo, whereas 100 mg inhibited aggregation by nearly 100%. CONCLUSIONS: -Lotrafiban provides dose-dependent platelet inhibition when administered to a range of patients with atherosclerosis. The level of platelet inhibition appears to correlate with bleeding risk and drug tolerability.

Does concurrent prescription of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs substantially increase the risk of upper gastrointestinal bleeding?

BACKGROUND: A 15-fold increased risk of gastrointestinal bleeding has been reported with concurrent use of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs. Recent guidance cautions against concurrent prescription, particularly in older people. AIM: To quantify the risk of gastrointestinal bleeding associated with current exposure to non-steroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, and both drugs concurrently. METHODS: We conducted a case-control analysis of 11,261 cases with upper gastrointestinal bleeding and 53,156 controls matched by gender, age and general practice from computerized primary care data. We coupled this with self-controlled case series analysis. RESULTS: Both drugs were associated with a twofold increased risk of gastrointestinal bleeding (odds ratio =2.38, 95% confidence interval 2.08-2.72 for selective serotonin reuptake inhibitors and odds ratio = 2.15, 95% confidence interval 2.02-2.28 for non-steroidal anti-inflammatory drugs). This increased risk was marginally higher for concurrent prescription (odds ratio = 2.93, 95% confidence interval 2.25-3.82). The self-controlled analysis showed a greater incidence rate ratio for gastrointestinal bleeding with non-steroidal anti-inflammatory drugs (2.71, 95% confidence interval 2.51-2.91) and lower incidence rate ratio with selective serotonin reuptake inhibitors (1.71, 95% confidence interval 1.48-1.98). The incidence rate ratio when both drugs were combined was 3.25, 95% confidence interval 1.95-5.42. Estimates were similar after restricting to people over 80 years of age. Increased risk of gastrointestinal bleeding was not specifically related to class of non-steroidal anti-inflammatory drugs and was similar when we looked at tricyclic anti-depressants. CONCLUSIONS: Our study suggests that the risk of gastrointestinal bleeding is not substantially increased when non-steroidal anti-inflammatory drugs and selective serotonin reuptake inhibitors are prescribed together, compared with their use alone.

A comparison of the recording of comorbidity in primary and secondary care by using the Charlson Index to predict short-term and long-term survival in a routine linked data cohort.

OBJECTIVE: Hospital admission records provide snapshots of clinical histories for a subset of the population admitted to hospital. In contrast, primary care records provide continuous clinical histories for complete populations, but might lack detail about inpatient stays. Therefore, combining primary and secondary care records should improve the ability of comorbidity scores to predict survival in population-based studies, and provide better adjustment for case-mix differences when assessing mortality outcomes. DESIGN: Cohort study. SETTING: English primary and secondary care 1 January 2005 to 1 January 2010. PARTICIPANTS: All patients 20 years and older registered to a primary care practice contributing to the linked Clinical Practice Research Datalink from England. OUTCOME: The performance of the Charlson index with mortality was compared when derived from either primary or secondary care data or both. This was assessed in relation to short-term and long-term survival, age, consultation rate, and specific acute and chronic diseases. RESULTS: 657,264 people were followed up from 1 January 2005. Although primary care recorded more comorbidity than secondary care, the resulting C statistics for the Charlson index remained similar: 0.86 and 0.87, respectively. Higher consultation rates and restricted age bands reduced the performance of the Charlson index, but the index's excellent performance persisted over longer follow-up; the C statistic was 0.87 over 1 year, and 0.85 over all 5 years of follow-up. The Charlson index derived from secondary care comorbidity had a greater effect than primary care comorbidity in reducing the association of upper gastrointestinal bleeding with mortality. However, they had a similar effect in reducing the association of diabetes with mortality. CONCLUSIONS: These findings support the use of the Charlson index from linked data and show that secondary care comorbidity coding performed at least as well as that derived from primary care in predicting survival.

Decreased fertility rates in 9639 women diagnosed with inflammatory bowel disease: a United Kingdom population-based cohort study.

BACKGROUND: Clinical studies have reported reduced fertility in women with inflammatory bowel disease (IBD). AIM: To compare fertility rates in women with IBD to those in women without IBD and assess whether the relative fertility differed following IBD diagnosis, flares and surgery. METHODS: Women aged 15-44 years in 1990-2010 were identified from a UK primary care database. We estimated overall and age-specific fertility rates by 5-year age bands for women with and without IBD. We used Poisson regression to calculate adjusted fertility rate ratios (AFRR), adjusted for age, smoking and socioeconomic deprivation. RESULTS: There were 46.2 live births per 1000 person-years [95% confidence interval (95% CI); 44.6-47.9] in 9639 women with IBD and 49.3 (95% CI 49.2-49.5) in 2 131 864 without (AFRR: 0.93; 95% CI: 0.89-0.96). Excluding periods of contraception use, the AFRR was 0.99 (95% CI: 0.95-1.03). Before diagnosis, the AFRR for women with ulcerative colitis (UC) was 1.07 (95% CI: 0.99-1.16) and was 0.88 (95% CI: 0.81-0.97) for women with CD. After diagnosis, AFRRs were 0.87 (95% CI: 0.82-0.94) for CD and 0.92 (95% CI: 0.86-1.00) for UC. The fertility rate was lower following flares (AFRR: 0.70; 95% CI: 0.59-0.82) or surgery (AFRR: 0.84; 95% CI: 0.77-0.92). Women with pouch and non-pouch surgery had similar overall fertility though the reduction after surgery was greater for pouches (AFRR: 0.48; 95% CI: 0.23-0.99). CONCLUSIONS: Women with Crohn's disease have marginally lower fertility rates. These rates decreased following flares and surgical interventions. Fertility rates returned almost to normal when women were not prescribed contraception but the reduction following surgical intervention remained. As the lifetime effect of pouch vs. nonpouch surgery on fertility is small, the reduction post-pouch surgery should be interpreted with caution.

Risk of malignancy in diagnosed coeliac disease: a 24-year prospective, population-based, cohort study.

BACKGROUND: There is recent evidence from studies of hospitalized and of undiagnosed patients that the risk of lymphoma for people with coeliac disease may be lower than previously thought. In addition, there have been no precise estimates of small bowel lymphoma risk due to a lack of population data. AIM: To examine these and other malignant risks in a cohort of patients more typical of those seen in routine clinical practice. METHODS: A prospective cohort study of incident malignancy rates in patients with coeliac disease in southern Derbyshire compared with general population figures. RESULTS: During 5684 person years of follow-up 31 malignancies (excluding non-melanoma skin cancer) occurred in comparison with 30.30 expected [standardized incidence ratio (SIR) 1.02 (0.69-1.45)]. There were four non-Hodgkin's lymphomas (0.69 expected) SIR 5.81 (1.58-14.86), of which one originated in small bowel (0.02 expected) SIR 40.51 (1.03-225.68). GI malignancy occurred in nine (5.71 expected) SIR 1.58 (0.72-2.99), and breast cancer in three (5.08 expected) SIR 0.59 (0.12-1.73). CONCLUSIONS: There is no increase in the risk of incident malignancy in this population and the risk of non-Hodgkin's lymphoma in general or of the small bowel is lower than previously found from UK coeliac cohorts.

Monitoring methotrexate-induced hepatic fibrosis in patients with psoriasis: are serial liver biopsies justified?

BACKGROUND: Reports that up to 26% of subjects with psoriasis develop cirrhosis have led to a recommendation of serial liver biopsies after each cumulative dose of 1500 mg of methotrexate. AIM: To evaluate the progression of liver injury in patients with psoriasis and the impact of monitoring by liver biopsy on their management. METHODS: One hundred and twenty-one liver biopsies from 66 subjects (aged 11-79 years) with psoriasis, receiving a median cumulative dose of 3206 mg of methotrexate over a period of 280.5 weeks, were evaluated. RESULTS: The assessment of advanced fibrosis according to the Ishak system (>or= 4) correlated perfectly with that of the Scheuer system (>or= 3) and poorly with that of the Roenigk scale (>or= 3b) (r2 = 1.0 and 0.31, respectively). Two of 24 pre-treatment biopsies showed advanced fibrosis and both subjects were heavy drinkers. The cumulative probabilities of advanced fibrosis (Ishak >or= 4) were 0%, 2.6%, 2.6%, 8.2% and 8.2% at cumulative doses of 1500, 3000, 4500, 5000 and 6000 mg, respectively. None of the subjects developed cirrhosis during follow-up or discontinued therapy on the basis of liver biopsy findings. CONCLUSIONS: Advanced hepatic fibrosis with low-dose methotrexate therapy is much less frequent than previously reported. Pre-treatment or monitoring liver biopsies in accordance with the current guidelines have little impact on patient management.

Risk of vascular disease in adults with diagnosed coeliac disease: a population-based study.

BACKGROUND: It has been suggested that vascular disease mortality may be reduced in coeliac disease because of lower levels of blood pressure, cholesterol and body mass. AIM: To examine whether people with coeliac disease are at reduced risk of various vascular diseases. METHODS: We identified 3,790 adults with diagnosed coeliac disease and 17,925 age- and sex-matched controls in the General Practice Research Database. We estimated odds ratios for diagnosed hypertension, hypercholesterolaemia and atrial fibrillation and hazard ratios for myocardial infarction and stroke. RESULTS: Adults with coeliac disease, compared with controls, were less likely to have had a diagnosis of hypertension [11% vs. 15%, odds ratio 0.68 (95% confidence interval: 0.60-0.76)] or hypercholesterolaemia [3.0% vs. 4.8%, odds ration 0.58 (95% confidence interval: 0.47-0.72)] but slightly more likely to have had atrial fibrillation [2.1% vs. 1.7%, odds ratio 1.26 (95% confidence interval: 0.97-1.64)]. The hazard ratio for myocardial infarction was 0.85 (95% confidence interval: 0.63-1.13), while the hazard ratio for stroke was 1.29 (95% confidence interval: 0.98-1.70). CONCLUSIONS: Although rates of myocardial infarction and stroke were not substantially different, adults with coeliac disease do have a lower prevalence of hypertension and hypercholesterolaemia compared with the general population. The effect of a gluten-free diet on cardiovascular risk factors should be determined before any screening programmes for coeliac disease are instituted.

Age and dose dependency of the pharmacokinetics and metabolism of bisphenol A in neonatal sprague-dawley rats following oral administration.

Previous studies demonstrated the rapid clearance of bisphenol A (BPA) from blood following oral administration to adult rats with the principal metabolite being BPA-monoglucuronide (BPA-glucuronide). Since the ontogeny of glucuronyl transferases (GT) differs with age, the pharmacokinetics of BPA were studied in neonatal animals. (14)C-BPA was administered via gavage at 1 or 10 mg/kg body weight to rats at postnatal day (pnd) 4, pnd 7, pnd 21, or to 11 week old adult rats (10 mg/kg dose only). Blood (neonates and adults) and selected tissues (neonates) were collected at 0.25, 0.75, 1.5, 3, 6, 12, 18, and 24 h postdosing. BPA and BPA-glucuronide in the plasma were quantified by high-performance liquid chromatography; radioactivity in the plasma and tissues was quantified by liquid scintillation spectrometry. The data indicate that neonatal rats at all three ages metabolized BPA to BPA-glucuronide, although an age dependency in the number and concentration of plasma metabolites was observed, consistent with the ontogeny of GT. BPA-glucuronide and BPA concentrations in the plasma were greater in neonates than in adults, except at 24 h postdosing, suggesting an immaturity in the development of hepatic excretory function in neonatal rats. Nevertheless, the half-lives for the elimination of BPA-glucuronide in plasma were more rapid in neonatal animals than in adults, likely due to reduced microflora beta-glucuronidase activity and an absence of enterohepatic recirculation. A dose dependency in the metabolism and pharmacokinetics of BPA administered to neonates was also observed with nearly complete metabolism of BPA to BPA-glucuronide (94-100% of the plasma radioactivity) at a dose of 1 mg/kg. This was in contrast to finding up to 13 different plasma metabolites observed at the 10 mg/kg dose. These data indicate that, from early in neonatal life through pnd 21, there is sufficient GT activity in rats to efficiently metabolize BPA to its nonestrogenic metabolite at low doses.

Metabolism and pharmacokinetics of bisphenol A (BPA) and the embryo-fetal distribution of BPA and BPA-monoglucuronide in CD Sprague-Dawley rats at three gestational stages.

The pharmacokinetics of bisphenol A (BPA), including the quantification of the major BPA metabolite BPA-monoglucuronide conjugate (BPA-glucuronide) was studied in Sprague-Dawley rats at different stages of gestation. 14C-BPA was administered orally at 10 mg BPA/kg body weight (0.2 mCi/rat) to nongravid rats and to other groups on gestation days (GD) 6, 14, and 17. GD 0 was when the vaginal smear was sperm positive or a copulatory plug was observed. Radioactivity derived from 14C-BPA was quantified in the maternal blood, selected tissues, and the embryo or fetus. BPA and BPA-glucuronide were quantified in maternal plasma and excreta. Additional rats were dosed orally at 10 mg 14C-BPA/kg (0.2 mCi/rat or 0.5 mCi/rat) on GD 11, 13, and 16 to further study the distribution of BPA and BPA-glucuronide to the embryo/fetal tissue. The tissue distribution, metabolism, or the rates or routes of excretion of BPA, or the plasma concentration-time profiles of BPA-glucuronide did not appear to be altered at any stage of gestation as compared to nonpregnant rats. In the GD 11 group, neither BPA nor BPA-glucuronide was detected in the yolk sacs or embryos, except for trace concentrations of BPA-glucuronide in the yolk sacs at 15 min postdosing. In the GD 13 group, both BPA and BPA-glucuronide were detected in the yolk sacs of the conceptus but not in the embryos/fetuses, except for BPA at 15 min. For the animals dosed with 0.2 mCi/rat on GD 16, both analytes were detected in the placentae at 15 min and 12 h, but not at 96 h. Traces of both analytes were detected in fetal tissue in two of five specimens at 15 min only. In rats dosed on GD 16 with 0.5 mCi/rat, the BPA-glucuronide and BPA concentrations in maternal plasma at 15 min were 1.7 and 0.06 mug equivalents (eq)/g plasma, respectively. At the same time postdosing in these animals, the placental BPA-glucuronide concentrations were lower (0.34 mug eq BPA [as glucuronide]/g), and the BPA concentrations were about equivalent (0.095 mug/g). Fetal BPA-glucuronide and BPA concentrations were markedly lower, 0.013 and 0.018 mug eq/g, respectively. Therefore, no selective affinity of either yolk sac/placenta or embryo/fetus for BPA or BPA metabolites relative to maternal plasma or tissues was observed in this study.

Review article: the economic impact of the irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a chronic functional disorder of the gastrointestinal system affecting a large number of people worldwide. Whilst it has no attributable mortality, it has substantial impact on patients' quality of life (QoL) and is associated with considerable healthcare resource use. AIM: To review the economic impact of IBS, firstly on the individual, secondly on healthcare systems internationally and thirdly to society. METHODS: Appropriate databases were searched for relevant papers using the terms: Irritable Bowel Syndrome; IBS; irritable colon; functional bowel/colonic disease; economics; health care/service costs; health expenditure/resources; health care/service utilisation; productivity. RESULTS: Irritable bowel syndrome impacts most substantially on patients' work and social life. Reduction in QoL is such that on average patients would sacrifice between 10 and 15 years of their remaining life expectancy for an immediate cure. Between 15% and 43% of patients pay for remedies. No studies quantify loss of earnings related to IBS. Direct care costs are substantial; 48% of patients incur some costs in any year with annual international estimates per patient of: USA $742-$7547, UK £90-£316, France €567-€862, Canada $259, Germany €791, Norway NOK 2098 (€262) and Iran $92. Minimising extensive diagnostic investigations could generate savings and has been shown as not detrimental to patients. Cost to industry internationally through absenteeism and presenteeism related to IBS is estimated between £400 and £900 per patient annually. CONCLUSIONS: Irritable bowel syndrome is associated with substantial costs to patients, healthcare systems and society. Considerable benefit could be obtained from effective interventions.